Indene compounds

ABSTRACT

The invention provides an indene compound represented by the following general formula (I): ##STR1## wherein R 1  means a lower alkyl group, R 2  and R 3  denote a lower alkyl group individually or an alkylenedioxy group in combination, and R 4  and R 5  mean individually a substituted or unsubstituted lower alkyl or aryl group or in combination a substituted or unsubstituted piperidino, piperazinyl or homopiperazinyl group together with the adjacent nitrogen atom, with a proviso that not both R 4  and R 5  are a methyl group at the same time.

This is a division of application Ser. No. 884,649 filed July 11, 1986now U.S. Pat. No. 4,762,927.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to indene compounds, and more specifically toindene compounds represented by the following general formula (I):##STR2## wherein R₁ means a lower alkyl group, R₂ and R₃ denote a loweralkyl group individually or an alkylenedioxy group in combination, andR₄ and R₅ mean individually a substituted or unsubstituted lower alkylor aryl group or in combination a substituted or unsubstitutedpiperidino, piperazinyl or homopiperazinyl group together with theadjacent nitrogen atom, with a proviso that not both R₄ and R₅ are amethyl group at the same time.

2. Description of the Prior Art

As indene compounds, 2,3-substituted-5,6-methylenedioxyindenes havealready been disclosed in U.S. Pat. No. 4,393,226. They have howeverbeen found dissatisfactory in the increasing effects of coronary bloodflow.

SUMMARY OF THE INVENTION

An object of this invention is to provide novel indene compounds whichare useful as therapeutic agents for angina pectoris and the like.

The present inventors have carried out a variety of investigations onindene compounds. As a result, it has been found that the above novelcompounds represented by the general formula (I) are excellent in theincreasing effects of coronary blood flow, antagonism of intracellularCa, etc., leading to completion of this invention.

In one aspect of this invention, there is thus provided an indenecompound represented by the following general formula (I): ##STR3##wherein R₁ means a lower alkyl group, R₂ and R₃ denote a lower alkylgroup individually or an alkylenedioxy group in combination, and R₄ andR₅ mean individually a substituted or unsubstituted lower alkyl or arylgroup or in combination a substituted or unsubstituted piperidino,piperazinyl or homopiperazinyl group together with the adjacent nitrogenatom, with a proviso that not both R₄ and R₅ are a methyl group at thesame time.

The indene compounds (I) of this invention have strong increasingeffects of coronary blood flow, and are hence useful as therapeuticagents for angina pectoris.

The above and other objects, features and advantages of the presentinvention will become apparent from the following description andappended claim.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

In the compounds (I) of this invention, as substituent groups for thelower alkyl groups represented by R₄ and R₅, may for example bementioned substituted or unsubstituted aryl groups, hydroxyl group,di(lower alkyl)amino groups, substituted or unsubstituted piperazinylgroups, piperidino group, etc. Illustrative examples of substituentgroups for the piperidino group, piperazinyl group and homopiperazinylgroup represented by R₄ and R₅ may include substituted or unsubstitutedbenzyl groups, aryl groups, lower alkyl groups, hydroxy lower alkylgroups, substituted or unsubstituted phenylcarbonyl groups and so on.

It should be borne in mind that the present invention embraces allisomers of the compounds represented by the general formula (I).

The indene compounds of this invention may be prepared, for example, byreacting an indene compound (III) with a secondary amine (II) inaccordance with the following reaction formula: ##STR4## wherein X meansa halogen atom and R₁, R₂, R₃, R₄ and R₅ have the same meaning asdefined above.

The above reaction may be carried out by stirring the reactants at roomtemperature or under ice cooling for several hours in a solvent such asdimethylsulfoxide.

The starting compound represented by the general formula (III) is also anovel compound prepared by the present inventors. It may be prepared,for example, in accordance with the following reaction scheme: ##STR5##

The compound (III) in which X is a chlorine atom, namely, the compound(IIIa) is obtained by bubbling hydrogen chloride gas at room temperaturein a methanol solution of the compound represented by the generalformula (IV), while the compound (III) in which X is a bromine atom,i.e., the compound (IIIb) is obtained by bubbling hydrogen chloride gasin the same methanol solution under ice-salt cooling to obtain themethoxy derivative (V) and then reacting the methoxy derivative (V) withphosphorus tribromide in chloroform as a solvent under ice cooling.

Among the secondary amines (II), the compounds in each of which R₄ meansa lower alkyl group and R₅ denotes, for example, a substituted orunsubstituted lower alkyl group are novel compounds. These novelcompounds include, for example,N-methyl-N-[4-[2-(1,3-benzothiazolyl)]benzyl]amine,N-methyl-N-[2-(4-isopropylthiophenyl)-2-hydroxyethyl]amine,N-methyl-N-[2-[4-(2-furanylcarbonyl)-1-piperazinyl]ethyl]amine,N-methyl-N-(2-piperidinoethyl)amine,N-methyl-N-[2-[4-[2-(4-isopropylthiophenyl)-2-hydroxyethyl]-1-piperazinyl]ethyl]amine.These novel compounds can be prepared, for example, in a manner whichwill later be described in detail in Referential Examples.

The thus-obtained indene compounds (I) of this invention may thereafterbe converted, by conventional method, into their inorganic salts such ashydrochlorides, hydrobromides and hydroperchlorides and their organicsalts such as fumarates, succinates, tartrates, maleates and oxalates,as needed.

[Effects]

The increasing effects of coronary blood flow and antagonism ofintracellular Ca of the compounds (I) of this invention were tested bythe following methods. Results are shown in Table 1.

(i) Increasing effects of coronary blood flow:

Their increasing effects of coronary blood flow were measured by theLangendorff method. After sacrificing each Hartley guinea pig having abody weight of approximately 250 g, its heart was removed promptly andthen connected to a Langendorff's perfusion apparatus. Krebs-Henseleitsolution (which contained 0.5% of defibrinated blood of guinea pig)gassed with 95%O₂ +5%CO₂ at 25° C. was perfused to the heart through theaorta countercurrently. While guiding the effluent to a droplet counterto determine the number of droplets, each test compound at aconcentration of 3×10⁻⁴ M dissolved in a physiological saline wasperfused through an aortic cannula at a flow rate of 0.1 ml per 10seconds. The change in the number of droplets induced by the testcompound was determined at an interval of 1 minute. The rate of coronaryvasodilation (%) was obtained through dividing the maximal valueobserved during 20 minutes after perfusing the test compound by thepretreatment value.

(ii) Antagonism of intracellular Ca:

The antagonism of intracellular Ca was measured by the Magnus method,using a herical strip of the thoracic aorta removed from each Wistar rathaving a body weight of approximately 200 g. Namely, two strips of aortaspecimens cut out from the same rat were thoroughly incubated under 1 gof resting load in a physiological salt solution (NaCl: 118 mM, KCl: 4.7mM, MgCl₂.6H₂ O: 0.54 mM, NaH₂ PO₄ : 1.0 mM, NaHCO₃ : 25 mM, EDTA:0.0027 mM, CaCl₂.2H₂ O: 2.5 mM, and glucose: 2.5 mM) aerated with 95%O₂+5%CO₂. After the equilibration period, the tissues were washed in acalcium-free physiological salt solution containing 1.0 mM EGTA and wereequilibrated. After one aortic strip was contracted by the test compoundof a concentration of 10⁻⁴ M in physiological saline and the other wascontracted by the physiological saline, norepinephrine was added to bothstrips to give a final concentration of 3×10⁻⁶ M. The tension developedby norepinephrine was recorded on a recorder through a force transducerand the phasic contraction Pd (control Ps) and tonic contraction Td(control Ts) were measured from its wave form.

Thereafter, two tissues were washed with the calcium-free nutrientsolution, and they were again contracted by the same amount ofnorepinephrine to determine their respective contractile heights Hd(control Hs). Then, their intracellular Ca inhibitory effects (%) werecalculated in accordance with the following equations.

    Inhibition of phasic contraction (%)=[1-(Pd/Hd)/(Ps/Hs)]×100

    Inhibition of tonic contraction (%)=[1-(Td/Hd)/(Ts/Hs)]×100

                  TABLE 1                                                         ______________________________________                                                Langerdorff method                                                                         Intracellular Ca                                                 in guinea pig                                                                              antagonism                                                       (3 × 10.sup.-4 M)                                                                    (10.sup.-4 M)                                                      Increase of    Phasic    Tonic                                      Compound* coronary blood flow                                                                          inhibition                                                                              inhibition                                 No.       (%)            (%)       (%)                                        ______________________________________                                        5b        46.1                                                                8b        18.8           56.6      57.1                                       12b       29.7           76.6      63.0                                       13b       19.9                                                                14b       29.8                                                                15b       24.2                                                                16b       45.7                                                                17b       89.4           60.7      54.0                                       18b       70.0           43.4      8.8                                        19b       42.3           39.4      36.6                                       20b       53.5           71.5      1.8                                        21b       45.1                                                                22b       30.3                                                                23b       28.3                                                                24b       34.3                                                                25b       39.5                                                                26b       65.9                                                                27b       108.8                                                               Control** 17.1           20.9      61.1                                       ______________________________________                                         *Indicated by Example number.                                                 **2n-Butyl-3-dimethylamino-5,6-methylenedioxyindene hydrochloride.       

Having generally described this invention, a further understanding canbe obtained by reference to certain specific examples which are providedherein for purpose of illustration only and are not intended to belimiting unless otherwise specified.

[Examples]

The present invention will hereinafter be described further by thefollowing Referential Examples and Examples:

REFERENTIAL EXAMPLE 1: Synthesis of2-n-butyl-3-chloro-5,6-methylenedioxyindene

Dissolved in 1 ml of methanol was 114 mg of2-n-butyl-3-(3,4-methylenedioxyphenyl)acrylaldehyde, into which hydrogenchloride gas was bubbled at room temperature for 5 minutes. The methanolwas distilled off under reduced pressure, and the residue was purifiedby column chromatography on silica gel (eluent: a 10:1 mixture ofn-hexane and ethyl acetate) to give 35 mg of2-n-butyl-3-chloro-5,6-methylenedioxyindene having a melting point of126°-128° C. as crystals (yield: 29%).

IR ν_(max) ^(KBr) cm⁻¹ :1470, 1325, 1030, 860, 710.

REFERENTIAL EXAMPLE 2: Synthesis of2-n-butyl-3-bromo-5,6-methylenedioxyindene (1)2-n-Butyl-3-methoxy-5,6-methylenedioxyindene:

Dissolved in 80 ml of methanol was 12 g of2-n-butyl-3-(3,4-methylenedioxyphenyl)acrylaldehyde, into which hydrogenchloride gas was blown under ice-salt cooling. Upon confirmation of fullconsumption of the raw material by thin-layer chromatography (eluent: a5:1 mixture of n-hexane and ether), the bubbling of hydrogen chloridegas was stopped. Water was added to the reaction mixture, followed byextraction of the resultant mixture, followed by extraction of theresultant mixture with ether. After the resultant ether solution waswashed with water, a saturated aqueous solution of sodiumhydrogencarbonate and water successively, the ether solution was driedover anhydrous magnesium sulfate and then concentrated under reducedpressure. The residue was purified by column chromatography on silicagel (eluent: a 10:1 mixture of n-hexane and ether) to give 11.4 g of2-n-butyl-3-methoxy-5,6-methylenedioxyindene as an oily substance(yield: 90%).

IR ν_(max) ^(neat) cm⁻¹ :1465, 1330, 1085, 1035.

(2) 2-n-Butyl-3-bromo-5,6-methylenedioxyindene:

Dissolved in 100 ml of chloroform was 9.3 g of2-n-butyl-3-methoxy-5,6-methylenedioxyindene, followed by a dropwiseaddition of 15.4 g of phosphorus tribromide over 1 hour under icecooling. After stirring the resultant mixture for further 4 hours, thereaction mixture was stirred for additional 4 hours at room temperature.The reaction mixture was washed with water, a 5% aqueous solution ofsodium hydroxide and water successively, dried over anhydrous magnesiumsulfate, and then concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel (eluent: a 20:1 mixtureof n-hexane and ether) to give 7.6 g of2-n-butyl-3-bromo-5,6-methylenedioxyindene having a melting point of63.0°-64.0° C. as crystals (yield: 68%).

IR ν_(max) ^(KBr) cm⁻¹ :1470, 1330, 1038, 650.

REFERENTIAL EXAMPLE 3:

Following the procedure of Referential Example 2 except for the use of2-n-propyl-3-(3,4-methylenedioxyphenyl)acrylaldehyde in place of the2-n-butyl-3-(3,4-methylenedioxyphenyl)acrylaldehyde, was obtained2-n-propyl-3-bromo-5,6-methylenedioxyindene having a melting point of96°-97° C. as crystals.

IR ν_(max) ^(KBr) cm⁻¹ :1465, 1320, 1235, 1030, 860.

REFERENTIAL EXAMPLE 4: Synthesis ofN-methyl-N-[4-[2-(1,3-benzothiazolyl)]benzyl]amine (1)2-(4-Bromomethylphenyl)-1,3-benzothiazole:

Refluxed for 1 hour was 150 ml of a carbon tetrachloride solution whichcontained 10 g of 2-(4-methylphenyl)-1,3-benzothiazole, 8.0 g ofN-bromosuccinimide (NBS) and 0.2 g of benzoyl peroxide. After allowingthe reaction mixture to cool down, the insoluble material was filteredoff and the filtrate was concentrated under reduced pressure. Theresidue was recrystallized from ethanol to give 8.0 g of colorlesscrystals having a melting point of 128°-130° C. (yield: 59%).

IR ν_(max) ^(KBr) cm⁻¹ :1475, 1220, 965, 755, 600.

(2) N-Methyl-N-[4-[2-(1,3-benzothiazolyl)]benzyl]amine:

To a liquid mixture consisting of 150 ml of a 25% aqueous methylaminesolution and 300 ml of tetrahydrofuran (THF), 7.2 g of2-(4-bromomethylphenyl)-1,3-benzothiazole was added under ice cooling.The resulting mixture was stirred for 1.5 hours. Thereafter, a saturatedaqueous solution of sodium chloride was added. The reaction mixture wasextracted with ethyl acetate. After washing the ethyl acetate solutionover water, the ethyl acetate solution was dried over anhydrousmagnesium sulfate (MgSO₄) and then concentrated under reduced pressure.The residue was purified by column chromatography on silica gel (eluent:a 10:1 mixture of chloroform and methanol) to give 5.0 g of crystalshaving a melting point of 75°-77° C. (yield: 83%).

IR ν_(max) ^(KBr) cm⁻¹ :1480, 1435, 1220, 1095, 960, 760.

REFERENTIAL EXAMPLE 5: Synthesis ofN-methyl-N-[2-(4-isopropylthiophenyl)-2-hydroxyethyl]amine (1)Isopropylthiobenzene:

To a solution containing 75 g of thiophenol in 500 ml ofdimethylformamide, 94 g of potassium carbonate was added under icecooling and the resulting mixture was stirred for 30 minutes.Thereafter, 126 g of isopropyl bromide was added dropwise over 1 hour.The reaction mixture was then stirred overnight at room temperature. Theinsoluble material was filtered off. The filtrate was poured into water,extracted with ether, and then washed with a dilute aqueous solution ofsodium hydrogencarbonate and water successively. The ether solution wasdried over anhydrous magnesium sulfate, followed by its concentrationunder reduced pressure to give 102 g of residue. The reaction productwas provided for the next reaction in its unpurified form.

IR ν_(max) ^(neat) cm⁻¹ :2950, 1578, 1470, 1235, 735, 685.

(2) 4-Isopropylthioacetophenone:

To a solution containing 165 g of anhydrous stannic chloride in 200 mlof dichloromethane, 50 g of acetyl chloride was added dropwise over 10minutes under ice cooling. After stirring the resulting mixture at thesame temperature for 20 minutes, a solution of 88 g ofisopropylthiobenzene in 200 ml of dichloromethane was added dropwiseover 30 minutes. After stirring the reaction mixture at the sametemperature for 1 hour and then at room temperature for 30 minutes, itwas poured into ice water. The dichloromethane layer was washed withwater, dried over anhydrous magnesium sulfate and then concentratedunder reduced pressure. The residue was distilled under reduced pressureto obtain 36.9 g of a fraction at 122° C./0.4 Torr (yield: 33%).

IR ν_(max) ^(neat) cm⁻¹ :2960, 1670, 1585, 1265, 1095, 820.

(3) 4-Isopropylthio-α-bromoacetophenone:

To a solution containing 36.9 g of 4-isopropylthioacetophenone and 1 mlof 48% hydrobromic acid in 330 ml of acetic acid, a solution of 30.3 gof bromine in 20 ml of acetic acid was added dropwise over 1 hour at 10°C. After adding ether and then washing the resultant mixture with water,a saturated aqueous solution of sodium hydrogencarbonate, an aqueoussolution of sodium thiosulfate and water successively, the ethereallayer was dried over anhydrous magnesium sulfate and then concentratedunder reduced pressure. The residue was recrystallized from ethanol togive 40 g of crystals having a melting point of 54°-56° C. (yield: 77%).

IR ν_(max) ^(KBr) cm⁻¹ :2960, 1685, 1585, 1085, 805.

(4) 4-Isopropylthiophenyloxirane:

Added at room temperature to a solution of 1.23 g of4-isopropylthio-α-bromoacetophenone in 15 ml of methanol was 170 mg ofsodium boron hydride, followed by stirring of the resulting mixture for15 minutes. After adding ether to the reaction mixture and then washingit with water, the mixture was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was dissovled in 20 mlof THF, to which 20 ml of a 3% aqueous solution of sodium hydroxide wasadded at room temperature. The thusprepared mixture was stirred for 15minutes. The mixture was extracted with ether, washed with water, driedover anhydrous magnesium sulfate, and then concentrated under reducedpressure to give 1.0 g of an oily substance. The reaction product wasprovided for the next reaction in its unpurified form. NMR(CDCl₃) δ:##STR6## 3.36 (1H, m, J=6Hz --CH<), 3.76-3.86 (1H, m, CH-Ph),7.12-7.40(4H, arom.).

(5) N-Methyl-N-[2-(4-isopropylthiophenyl)-2-hydroxyethyl]amine:

A solution of 842 mg of 4-isopropylthiophenyloxirane in 30 ml ofmethanol which contained 20% of methylamine was reacted at 70° C. in asealed tube for 41 hours. After allowing the reaction mixture to cooldown, the reaction mixture was concentrated under reduced pressure andthe residue was purified by column chromatography on silica gel (eluent:a 10:1 mixture of chloroform and methanol) to give 428 mg of an oilysubstance.

NMR(CDCl₃) δ: ##STR7## 2.48 (3H, s, CH₃ --N), 2.74-3.86 (2H, m, CH₂--N), 3.16-3.36 (2H, NH, OH), 3.40 (1H, m, J=7Hz, --CH<), 4.74-4.90 (1H,m, CH--Ph), 7.30-7.60 (4H, arom.).

REFERENTIAL EXAMPLE 6: Synthesis ofN-methyl-N-[2-(4-(2-furanylcarbonyl)-1-piperazinyl)ethyl]amine (1)1-(2-Furanylcarbonyl)-4-[2-(2-furanylcarbonyloxy)ethyl]piperazine:

To a solution of 12.5 g of 1-piperazine ethanol and 23.7 g oftriethylamine in 200 ml of benzene, a solution of 22.6 g of2-furancarbonyl chloride in 50 ml of benzene was gradually addeddropwise under ice cooling. After the addition, the reaction mixture wasstirred for further 2 hours. It was then washed with a saturated aqueoussolution of sodium hydrogencarbonate and water successively, dried overanhydrous magnesium sulfate and then concentrated under reduced pressureto give 25.2 g of an oily substance. The reaction product was providedfor the next step in its unpurified form.

NMR(CDCl₃) δ: ##STR8## 2.80 (2H, t, J=6Hz, CH₂ N<), ##STR9## 4.46 (2H,t, J=6Hz, CH₂ O--), 6.46-7.66 (6H, arom.).

(2) 1-(2-Furanylcarbonyl)-4-(2-hydroxyethyl)piperazine:

To a solution of 3.7 g of1-(2-furanylcarbonyl)-4-(2-(2-furanylcarbonyloxy)ethyl)piperazine in 30ml of methanol, 12.5 ml of a 3% aqueous solution of sodium hydroxide wasadded at room temperature. The resulting mixture was stirred for 40minutes. After distilling off the methanol under reduced pressure, theresidue was taken up in chloroform and then washed once with a saturatedaqueous solution of sodium chloride. The chloroform layer was dried overanhydrous magnesium sulfate and then concentrated under reducedpressure. The residue was purified by column chromatography on silicagel (eluent: a 10:1 mixture of chloroform and methanol) to give 2.3 g ofan oily substance (yield: 82%).

NMR(CDCl₃) δ: ##STR10## 3.68 (2H, t, J=6Hz, OCH₂), ##STR11##6.48-7.54(3H, arom.).

(3) 1-(2-Furanylcarbonyl)-4-(2-chloroethyl)piperazine:

Dissolved in 20 ml of thionyl chloride was 1.76 g of1-(2-furanylcarbonyl)-4-(2-hydroxyethyl)piperazine. The resultingmixture was stirred at room temperature for 7.5 hours. The thionylchloride was distilled off under reduced pressure and the residue waspoured into cold water. After alkalinization of the resulting aqueoussolution with sodium carbonate, the solution was extracted with benzeneand the benzene layer was washed with water. The benzene layer was driedover anhydrous magnesium sulfate and thereafter concentrated underreduced pressure to give 1.2 g of an oily substance. The reactionproduct was provided for the next step in its unpurified form.

IRν_(max) ^(neat) cm⁻¹ :2800, 1610, 1560, 1420, 1260, 1000, 750.

(4) N-Methyl-N-[2-(4-(2-furanylcarbonyl)-1-piperazinyl)ethyl]amine:

A solution of 1.0 g of 1-(2-furanylcarbonyl)-4-(2-chloroethyl)piperazineand 200 mg of sodium iodide in 40 ml of methanol which contained 25% ofmethylamine was reacted at 70° C. in a sealed tube for 24 hours. Afterallowing the reaction mixture to cool down, the reaction mixture wasconcentrated under reduced pressure and the residue was purified bycolumn chromatography on silica gel (eluent: a 20:1:0.1 mixture ofchloroform, methanol, and methanol containing 40% methylamine) to give800 mg of crystals (yield: 82%).

IR ν_(max) ^(neat) cm⁻¹ :2940, 2800, 1610, 1560, 1430, 1010, 760.

REFERENTIAL EXAMPLE 7: Synthesis of N-methyl-N-(2-piperidinoethyl)amine

A solution of 8.0 g of N-(2-chloroethyl)piperidine hydrochloride and 0.5g of sodium iodide in 60 ml of methanol which contained 40% ofmethylamine was reacted at 70° C. in a sealed tube for 20 hours. Afterallowing the reaction mixture to cool down, the reaction mixture wasconcentrated under reduced pressure. The residue was added with ether,followed by a further addition of 10 g of ground sodium hydroxide. Theresulting mixture was stirred for 2 hours. The insoluble material wasfiltered off and the filtrate was concentrated under the atmosphericpressure. The residue was distilled under reduced pressure to give 4.5 gof a fraction at 80° C./18 Torr (yield: 73%).

NMR(CDCl₃) δ: ##STR12##

REFERENTIAL EXAMPLE 8: Synthesis ofN-methyl-N-[2-[4-[2-(4-isopropylthiophenyl)-2-hydroxyethyl)]-1-piperazinyl]ethyl]amine(1) 4-Isopropylthio-α-[4-(2-hydroxylethyl)-1-piperazinyl]acetophenone:

To a solution containing 3.6 g of 1-piperazine ethanol and 3.9 g ofsodium carbonate in 30 ml of dimethylsulfoxide, a solution of 5.0 g of4-isopropylthio-α-bromacetophenone in 20 ml of dimethylsulfoxide wasgradually added dropwise under ice cooling. After the addition, thereaction mixture was stirred at room temperature for 1 hour, added witha saturated aqueous solution of sodium chloride and then extracted withchloroform. The chloroform layer was washed once with a saturatedaqueous solution of sodium chloride. After drying the chloroform layerover anhydrous magnesium sulfate, it was concentrated under reducedpressure and the residue was purified by column chromatography on silicagel (eluent: a 10:1 mixture of chloroform and methanol) to give 4.8 g ofcrystals (yield: 81%).

IR [_(max) ^(KBr) cm⁻¹ :3400, 2940, 2820, 1680, 1590, 1165, 975.

(2) 4-Isopropylthio-α-[4-(2-chloroethyl)-1-piperazinyl]acetophenone:

After stirring a solution of 4.8 g of4-isopropylthio-α-[4-(2-hydroxyethyl)-1-piperazinyl]acetophenone in 40ml of thionyl chloride for 4 hours under ice cooling, the solution wasconcentrated under reduced pressure. Ice water was added to the residue,the resulting mixture made alkaline with sodium carbonate and thenextracted with ethyl acetate. After washing the ethyl acetate layer withwater, it was dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: a 15:1 mixture of chloroform andacetone) to give 2.3 g of crystals (yield: 45%). Since the reactionproduct was unstable, it was immediately provided for the next step.

IR ν_(max) ^(KBr) cm⁻¹ :2930, 2800, 1670, 1580, 1215, 1090, 970, 815.

(3)4-Isopropylthio-α-[4-(2-(N-methylamino)ethyl)-1-piperazinyl]acetophenone:

A solution of 3.45 g of4-isopropylthio-α-[4-(2-chloroethyl)-1-piperazinyl]acetophenone and 0.5g of potassium iodide in 50 ml of methanol which contained 20% ofmethylamine was reacted at 60° C. in a sealed tube for 10 hours. Afterallowing the reaction mixture to cool down, it was purified by columnchromatography on silica gel (eluent: a 5:1:0.1 mixture of chloroform,methanol, and methanol containing 40% of methylamine) to give 2.5 g ofan oily substance (yield: 74%).

IR ν_(max) ^(neat) cm⁻¹ :3300, 2925, 2800, 1665, 1585, 1440, 1150, 750.

(4)N-Methyl-N-[2-(4-(2-(4-isopropylthiophenyl)-2-hydroxyethyl)-1-piperazinyl)ethyl]amine:

After gradually adding 0.5 g of sodium boron hydride to 4.0 g of4-isopropylthio-α-[4-(2-(N-methylamino)ethyl)-1-piperazinyl]acetophenonein 50 ml of methanol under ice cooling, the resulting mixture wasstirred for 1.5 hours. It was concentrated under reduced pressure andthe residue was purified by column chromatography on silica gel (eluent:a 5:1:0.1 mixture of chloroform, methanol, and methanol containing 40%of methylamine) to give 3.1 g of an oily substance (yield: 77%).

IR ν_(max) ^(neat) cm⁻¹ :3100, 2920, 2800, 1440, 1150, 820.

As other secondary amines which are employed in subsequent Examples,commercial products or those synthesized by known processes were used.

EXAMPLE 1: Synthesis of2-n-butyl-3-diethylamino-5,6-methylenedioxyindene

To a solution containing 300 mg of diethylamine and 430 mg of sodiumcarbonate in 6 ml of dimethylsulfoxide, 600 mg of2-n-butyl-3-bromo-5,6-methylenedioxyindene was added at roomtemperature. The reaction mixture was stirred for 5 hours. Aftercompletion of the reaction, the reaction mixture was added with asaturated aqueous solution of sodium hydrogencarbonate and thenextracted with ether. The ethereal layer was washed with water, driedover anhydrous magnesium sulfate and then concentrated under reducedpressure. The residue was purified by column chromatography on silicagel (eluent: a 10:1 mixture of n-hexane and ether) to give 380 mg of anoily substance (yield: 65%).

NMR(CDCl₃) δ: .88-1.04 (3H, m, --CH₃), 1.08 (6H, t, J=8Hz, N(CH₂ CH₃)₂),1.26-1.76 (4H, m, --CH₂ CH₂ --), ##STR13## 2.60 (4H, q, J=8Hz, N--(CH₂--CH₃)₂), 4.30 (1H, s, CH--N), 6.04 (2H, s, O--CH₂), 6.42 (1H, s, CH═C),6.82 (1H, s, arom.), 7.14 (1H, s arom.).

IR ν_(max) ^(neat) cm⁻¹ :2960, 1470, 1320, 1040.

The above compound was dissolved in ether, into which hydrogen chloridegas was then blown to convert it into its corresponding hydrochloride.Melting point: 139°-141.5° C..

IR ν_(max) ^(KBr) cm⁻¹ :2920, 2670-2100, 1470, 1320, 1225, 1030, 930.

EXAMPLES 2-28:

Using the secondary amines shown in the Referential Examples and knownsecondary amines instead of diethylamine employed in Example 1,compounds shown in Table 2 were separately obtained in the same manneras in Example 1.

                                      TABLE 2-1                                   __________________________________________________________________________     ##STR14##                                                                    Compound                                    Yield                                                                             m.p.                          Example                                                                            R.sub.4                                                                          R.sub.5                   Salt                                                                             Appearance                                                                           (%) (°C.)                  __________________________________________________________________________    2a   CH.sub.3                                                                         n-Bu                         oily   86                                2b   "  "                         .HCl                                                                             crystalline                                                                              131-133                       3a   CH.sub.3                                                                          ##STR15##                   crystalline                                                                          96  89.5-91.0                     4a                                                                                  ##STR16##                      crystalline                                                                          94  54.5-56.5                     4b   "                            .HCl                                                                             crystalline                                                                              191-193                                                                       (decomp'd)                    5a                                                                                  ##STR17##                      oily   98                                5b   "                            .HCl                                                                             crystalline                                                                              188-190                                                                       (decomp'd)                    6a   CH.sub.3                                                                          ##STR18##                   crystalline                                                                          93  91-93                         6b   "  "                         .HCl                                                                             crystalline                                                                              191.5-192.5                   7a   CH.sub.3                                                                          ##STR19##                   oily   90                                7b   "  "                         .HCl                                                                             crystalline                                                                              168-173                                                                       (decomp'd)                    8a   CH.sub.3                                                                          ##STR20##                   oily   76                                8b   "  "                         .HCl                                                                             crystalline                                                                              145-152                                                                       (decomp'd)                    9a   CH.sub.3                                                                          ##STR21##                   oily   98                                9b   "  "                         .HCl                                                                             crystalline                                                                              174.0-175.5                   10a                                                                                 ##STR22##                      oily   85                                10b  "                            .HCl                                                                             crystalline                                                                              185-189                                                                       (decomp'd)                    11a                                                                                 ##STR23##                      crystalline                                                                          88  128-130                       11b  "                            .HCl                                                                             crystalline                                                                              145-150                                                                       (decomp'd)                    12a                                                                                 ##STR24##                      crystalline                                                                          93  83-85                         12b  "                            .HCl                                                                             crystalline                                                                              180-183                                                                       (decomp'd)                    13a                                                                                 ##STR25##                      amorphous                                                                            95                                13b  "                            .HCl                                                                             crystalline                                                                              118-122                       14a                                                                                 ##STR26##                      amorphous                                                                            76                                14b  "                            .HCl                                                                             crystalline                                                                              120-125                       15a                                                                                 ##STR27##                      amorphous                                                                            76                                15b  "                            .HCl                                                                             crystalline                                                                              150-155                       16a  CH.sub.3                                                                         CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                                        oily   41                                16b  "  "                         .HCl                                                                             crystalline                                                                              159-163                                                                       (decomp'd)                    17a                                                                                 ##STR28##                      crystalline                                                                          83  66.0-67.5                     17b  "                            .HCl                                                                             crystalline                                                                              155.0-158.0                   18a                                                                                 ##STR29##                      oily   95                                18b  "                            .HCl                                                                             crystalline                                                                              149.0-152.0                   19a                                                                                 ##STR30##                      oily   85                                19b  "                            .HCl                                                                             crystalline                                                                              154.0-157.0                   20a                                                                                 ##STR31##                      crystalline                                                                          81  82.0-84.0                     20b  "                            .HCl                                                                             crystalline                                                                              155.0-158.0                   21a  CH.sub.3                                                                         CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                               oily   55                                21b  "  "                         .HCl                                                                             crystalline                                                                              168.0-171.0                   22a  CH.sub.3                                                                         CH.sub.2 CH.sub.2 N(C.sub.2 H.sub.5).sub.2                                                                 oily   66                                22b  "  "                         .HCl                                                                             crystalline                                                                              120.0-124.0                   23a  CH.sub.3                                                                          ##STR32##                   oily   64                                23b  "  "                         .HCl                                                                             crystalline                                                                              116.0-120.0                   24a                                                                                 ##STR33##                      oily   80                                24b  "                            .HCl                                                                             crystalline                                                                              195-196                                                                       (decomp'd)                    25a                                                                                 ##STR34##                      oily   46                                25b  "                            .HCl                                                                             crystalline                                                                              155-160                       26a                                                                                 ##STR35##                      oily   91                                26b  "                            .HCl                                                                             crystalline                                                                              177-180                                                                       (decomp'd)                    27a  CH.sub.3                                                                          ##STR36##                   oily   79                                27b  "  "                         .HCl                                                                             crystalline                                                                              179-184                                                                       (decomp'd)                    28a                                                                                 ##STR37##                      oily   95                                28b  "                            .HCl                                                                             crystalline                              __________________________________________________________________________     Note: In the compounds of Examples 28a and 28b, R.sub.1 is a npropyl          group.                                                                        Note: The compound of Example 7a is a diastereomer. The hydrochlorides in     Examples 7b, 27a and 27b are each a mixture of diastereomers.            

                                      TABLE 2-2                                   __________________________________________________________________________         Compound                                                                 Example                                                                            (see, Table 2-1)                                                                      NMR (CDCl.sub.3) δ              IR ν.sub.max.sup.nea                                                       t or                       __________________________________________________________________________                                                       KBr cm.sup.-1              2a                                                                                          ##STR38##                            2930, 1465, 1320,                                                             1040                       2b   .HCl                                          2950, 2700-2100,                                                              1460,                                                                         1320, 1225, 1030, 930      3a                                                                                          ##STR39##                            2920, 1590, 1495,                                                             1465, 1320, 1030,          4a                                                                                          ##STR40##                            2920, 1460, 1310,                                                             1040                       4b   .HCl                                          2920, 2680-2100,                                                              1470,                                                                         1330, 1030, 930            5a                                                                                          ##STR41##                            2925, 1595, 1460,                                                             1290, 1090, 730            5b   .HCl                                          2920, 2680-2100,                                                              1600,                                                                         1470, 1330, 1280,                                                             1100,                                                                         1030                       6a                                                                                          ##STR42##                            2920, 1460, 1310,                                                             1035, 725                  6b   .HCl                                          2920, 2700-2150,                                                              1470,                                                                         1325, 1230, 1020           7a   (diastereomer)                                                                         ##STR43##                            3400, 2950, 1460,                                                             1320, 1035                               ##STR44##                            3400, 2950, 1460,                                                             1318, 1035                 7b   (diastereomer                                 3330, 2950,                                                                   2730-2200,                      mixture)                                      1470, 1320, 1230,                                                             1030                            .HCl                                                                     8a                                                                                          ##STR45##                            2920, 1615, 1460,                                                             1280, 1030, 750            8b   .HCl                                          2920, 2720-2100,                                                              1620,                                                                         1475, 1420, 1320,                                                             1280,                                                                         1030                       9a                                                                                          ##STR46##                            2925, 1460, 1320,                                                             1040,                      9b   .HCl                                          2920, 2720-2100,                                                              1475,                                                                         1320, 1020, 925            10a                                                                                         ##STR47##                            2925, 1460, 1320,                                                             1135, 1035                 10b  .HCl                                          2920, 2720-2100,                                                              1470,                                                                         1325, 1030, 925            11a                                                                                         ##STR48##                            2920, 1590, 1460,                                                             1310, 1230, 1030, 750      11b  .HCl                                          2920, 2700-2100,                                                              1590,                                                                         1470, 1330, 1030           12a                                                                                         ##STR49##                            2925, 1470, 1320,                                                             1145, 1035, 865            12b  .HCl                                          2920, 2700-2100,                                                              1470,                                                                         1330, 1030                 13a                                                                                         ##STR50##                            2925, 1620, 1480,                                                             1280, 1095                 13b  .HCl                                          2925, 2700-2100,                                                              1620,                                                                         1460, 1410, 1280,                                                             1090,                                                                         1030                       14a                                                                                         ##STR51##                            2925, 1625, 1580,                                                             1460, 1325, 1125           14b  .HCl                                          2925, 2700-2100,                                                              1625,                                                                         1590, 1460, 1410,                                                             1325,                                                                         1230, 1110, 1030           15a                                                                                         ##STR52##                            2925, 1590, 1460,                                                             1320, 1120, 750            15b  .HCl                                          2925, 2700-2100,                                                              1590,                                                                         1460, 1410, 1330,                                                             1240,                                                                         1120, 1030                 16a                                                                                         ##STR53##                            2925, 1460, 1310,                                                             1035, 750                  16b  .HCl                                          2920, 2700-2100,                                                              1470,                                                                         1320, 1030                 17a                                                                                         ##STR54##                            2925, 1460, 1310,                                                             1030, 860                  17b  .HCl                                          2920, 2700-2100,                                                              1475,                                                                         1330, 1030                 18a                                                                                         ##STR55##                            2925, 1460, 1320,                                                             1150, 1035, 935, 850,                                                         750                        18b  .HCl                                          2925, 2700-2100,                                                              1475,                                                                         1330, 1030, 930            19a                                                                                         ##STR56##                            2920, 1460, 1320,                                                             1175, 1035, 860            19b  .HCl                                          2950, 2700-2100,                                                              1475,                                                                         1330, 1035, 930            20a                                                                                         ##STR57##                            3400, 2920, 2825,                                                             1460, 1320, 1030, 930      20b  .HCl                                          3350, 2920,                                                                   2700-2100,                                                                    1470, 1320, 1230,                                                             1025                       21a                                                                                         ##STR58##                            2930, 1460, 1315,                                                             1035, 860                  21b  .HCl                                          2925, 2750-220, 1470,                                                         1330, 1030                 22a                                                                                         ##STR59##                            2955, 1460, 1320,                                                             1040, 940, 860             22b  .HCl                                          2920, 2750-2100, 1470                                                         1320, 1030                 23a                                                                                         ##STR60##                            2930, 1465, 1320,                                                             1040, 865                  23b  .HCl                                          2920, 2750-2100,                                                              1470,                                                                         1320, 1030                 24a                                                                                         ##STR61##                            2925, 1460, 1320,                                                             1150, 1035, 940, 860       24b  .HCl                                          2950, 2700-2100,                                                              1470,                                                                         1320, 1030, 930            25a                                                                                         ##STR62##                            2925, 1460, 1310,                                                             1120, 1035, 935, 860       25b  .HCl                                          2920, 2700-2100,                                                              1470,                                                                         1320, 1030, 930            26a                                                                                         ##STR63##                            2925, 1460, 1320,                                                             1150, 1035, 860            26b  .HCl                                          2920, 2700-2100,                                                              1470,                                                                         1320, 1025, 920            27a  (diastereomer mixture)                                                                 ##STR64##                            3400, 2925, 1460,                                                             1310, 1150, 1035, 755      27b  (diastereomer                                 3350, 2950,                                                                   2700-2100,                      mixture)                                      1470, 1320, 1030                .HCl                                                                     28a                                                                                         ##STR65##                            2925, 1465, 1320,                                                             1035, 730                  28b  .HCl                                          2950, 2700-2100,                                                              1470,                                                                         1320,                      __________________________________________________________________________                                                       1030                   

Having now fully described the invention, it will be apparent to one ofthe ordinary skill in the art that many changes and modifications can bemade thereto without departing from the spirit or scope of the inventionas set forth herein.

What is claimed as new and is secured by letters patent:
 1. An indenecompound of the formula (I): ##STR66## wherein R₁ is a lower alkylgroup, R₂ and R₃ are, individually, a lower alkyl group or, incombination, are an alkylenedioxy group, and R₄ and R₅ are,individually, phenyl or benzyl, or a lower alkyl group which issubstituted with a di(lower alkyl) amino group, and salts thereof. 2.The indene compound of claim 1, wherein R₄ and R₅ are C₁₋₄ alkyl groups.3. The indene compound of claim 2, wherein R₄ and R₅ are methyl, ethylor n-butyl groups.
 4. The indene compound of claim 1, wherein R₄ and R₅are, individually, a phenyl or benzyl group.
 5. The indene compound ofclaim 1, wherein R₄ and R₅ are, individually, a lower alkyl groupsubstituted with a di(lower alkyl)amino group.
 6. The indene compound ofclaim 5, wherein said di(lower alkyl)amino group is a dimethyl ordiethyl amino group.
 7. The indene compound of claim 5, wherein R₄ andR₅ are, individually, selected from the group consisting ofdimethylaminoethyl, 3-dimethylaminopropyl and diethylaminoethyl groups.8. The indene compound of claim 1, wherein said salt is an inorganicsalt.
 9. The indene compound of claim 8, wherein said salt is selectedfrom the group consisting of hydrochlorides, hydrobromides andhydroperchlorides.
 10. The indene compound of claim 1, wherein said saltis an organic salt.
 11. The indene compound of claim 10, wherein saidsalt is selected from the group consisting of fumarates, succinates,tartrates, maleates and oxalates.
 12. An indene compound of the formula(I): ##STR67## wherein R₁ is a lower alkyl group, R₂ and R₃ are,individually, a lower alkyl group or, in combination, are analkylenedioxy group, and R₄ and R₅, individually, are selected from thegroup consisting of 4-[2-(1,3-benzothiazolyl)]benzyl,2-(4-isopropylthiophenyl)-2-hydroxyethyl,2-[4-(2-furanylcarbonyl)-1-piperazinyl]ethyl, 2-piperidinoethyl and2-[4-[2-(4-isopropylthiophenyl)-2-hydroxyethyl]-1-piperazinyl]-ethylgroups, and salts thereof.
 13. The indene compound of claim 12, whereinsaid salt is an inorganic salt.
 14. The indene compound of claim 13,wherein said salt is selected from the group consisting ofhydrochlorides, hydrobromides and hydroperchlorides.
 15. The indenecompound of claim 12, wherein said salt is an organic salt.
 16. Theindene compound of claim 15, wherein said salt is selected from thegroup consisting of fumarates, succinates, tartrates, maleates andoxalates.